Molecular Cancer Research最新文献

{"title":"β-catenin-cohesin ring-CEGRs/ALCDs axis activation contributes to the development of hepatoblastoma and fibrolamellar HCC.","authors":"Yasmeen Fleifil, Ruhi Gulati, Katherine Jennings, Ina Kycia, Alex Bondoc, Gregory Tiao, James Geller, Matthew Weirauch, Khashayar Vakili, Lubov Timchenko, Nikolai Timchenko","doi":"10.1158/1541-7786.MCR-25-0236","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0236","url":null,"abstract":"<p><p>The pediatric and adolescent liver cancers Hepatoblastoma (HBL) and Fibrolamellar hepatocellular carcinoma (FLC) are dangerous diseases requiring aggressive surgery, when feasible, and non-targeted toxic chemotherapy for a chance of cure, due to insufficient knowledge of underlying molecular mechanisms. We've previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called Cancer Enhancing Genomic Regions or Aggressive Liver Cancer Domains (CEGRs/ALCDs). In FLC, the fusion J-PKAc oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this paper, we found that all members of the cohesin ring - CTCF, Rad21, SMC1, SMC3 and STAG1 - and β-catenin-TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin-TCF4-p300 complex, are detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA-loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific DNAJB1-PKAc fusion oncogene. Implications: These studies provide evidence that J-PKAc-β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Signatures of Poor Prognosis in Merkel Cell Carcinoma: A Single-Institution Prospective Study.","authors":"Joshua D Smith, Apurva D Bhangale, Wenjin Gu, Collin Brummel, Elizabeth Gensterblum-Miller, Scott McLean, Paul W Harms, Kelly L Harms, Christopher K Bichakjian, Matthew E Spector, Ryan E Mills, J Chad Brenner","doi":"10.1158/1541-7786.MCR-24-1138","DOIUrl":"10.1158/1541-7786.MCR-24-1138","url":null,"abstract":"<p><p>Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end-users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV-positive), 11 (20.4 %) of which had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5 %), FAT1 (n = 9, 16.7 %), KMT2D (n = 9, 16.7 %), and RB1 (n = 7, 13.0 %). In 36 of 44 (81.8 %) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into COSMIC Tier 1 or Tier 2 cancer-related human genes. Implications: A combined genomics score incorporating tumor mutational burden and copy number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status, thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma.","authors":"Pengshu Fang, Emily R Wilson, Sydney N Larsen, Walter A Orellana, Margaret A Hall, Chris Stubben, Acramul Haque Kabir, Kajsa Affolter, Richard A Moffitt, Xiaoyang Zhang, Eric L Snyder","doi":"10.1158/1541-7786.MCR-25-0175","DOIUrl":"10.1158/1541-7786.MCR-25-0175","url":null,"abstract":"<p><p>Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classical or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classical subtype. Still, the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored. Here, we show that HNF4α-positive human PDAC tumors exhibit uniform expression of P2-isoforms but variable expression of P1 isoforms. To dissect the roles of each isoform in PDAC, we performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. We demonstrated that P1 isoforms are less compatible with growth and stronger transcriptional regulators than P2. Despite both isoforms sharing a common DNA-binding domain, P1 isoforms displayed stronger binding at HNF4α target genes, resulting in increased transcriptional activity. These findings provide a detailed characterization of HNF4α P1 and P2 isoforms and their distinct roles in PDAC biology. Implications: HNF4α isoforms exhibit heterogeneous expression in PDAC and have distinct effects on proliferation and gene expression, including markers of clinically relevant molecular subtypes.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine-Resistant Multiple Myeloma.","authors":"Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou","doi":"10.1158/1541-7786.MCR-24-0444","DOIUrl":"10.1158/1541-7786.MCR-24-0444","url":null,"abstract":"<p><p>Protein homeostasis is critical to the survival of multiple myeloma cells. Although this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity of multiple myeloma cells to the translation inhibitor omacetaxine. We hypothesized that understanding how multiple myeloma becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S multiple myeloma cell lines and compared them with parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nmol/L, compared with parental sensitivity of 24 to 54 nmol/L. As omacetaxine inhibits protein synthesis, we performed both RNA sequencing and ribosome profiling to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing a terminal oligopyrimidine sequence in their 5' untranslated region were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of terminal oligopyrimidine motif-containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine-naïve multiple myeloma cell lines, and a combination effect was observed in vivo. Primary multiple myeloma cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination therapy in patients with multiple myeloma, which have historically shown better responses to multiagent regimens.</p><p><strong>Implications: </strong>Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"611-621"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress.","authors":"Mary E Law, Zaafir M Dulloo, Samantha R Eggleston, Gregory P Takacs, Grace M Alexandrow, Young Il Lee, Mengxiong Wang, Brian Hardy, Hanyu Su, Bianca Forsyth, Parag Das, Pran K Datta, Chi-Wu Chiang, Abhisheak Sharma, Siva Rama Raju Kanumuri, Olga A Guryanova, Jeffrey K Harrison, Boaz Tirosh, Ronald K Castellano, Brian K Law","doi":"10.1158/1541-7786.MCR-24-0756","DOIUrl":"10.1158/1541-7786.MCR-24-0756","url":null,"abstract":"<p><p>New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described disulfide bond-disrupting agents activate DR5 by altering its disulfide bonding through inhibition of protein disulfide isomerases ERp44, AGR2, and PDIA1. Work presented in this article extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of caspase 8/caspase 3-mediated proapoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other endoplasmic reticulum (ER) stressors, including thapsigargin and tunicamycin, also alter DR5 disulfide bonding in various cancer cell lines, and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the integrated stress response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.</p><p><strong>Implications: </strong>Extreme ER stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"622-639"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11989202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell and Spatial Transcriptomics Reveal a Tumor-Associated Macrophage Subpopulation that Mediates Prostate Cancer Progression and Metastasis.","authors":"Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl","doi":"10.1158/1541-7786.MCR-24-0791","DOIUrl":"10.1158/1541-7786.MCR-24-0791","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression-free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their protumorigenic role. Blocking SPP1 in the RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment and increased CD8+ T-cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition in advanced prostate cancer.</p><p><strong>Implications: </strong>This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"653-665"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANGEL2 Modulates Wild-type TP53 Translation and Doxorubicin Chemosensitivity in Colon Cancer.","authors":"Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen","doi":"10.1158/1541-7786.MCR-24-0702","DOIUrl":"10.1158/1541-7786.MCR-24-0702","url":null,"abstract":"<p><p>Multiple lines of correlative evidence support a role for angel homolog 2 (ANGEL2), a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and survival of patients with cancer. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. In this study, we demonstrate that loss of ANGEL2 leads to a substantial decrease in the key tumor-suppressor protein tumor protein p53 (TP53). We show that ANGEL2 directly interacts with eukaryotic translation initiation factor 4E (EIF4E), the rate-limiting protein in cap-dependent translation. This interaction abrogates the ability of the TP53 translation repressor RNA-binding motif protein 38 to interact with EIF4E, thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased two-dimensional and three-dimensional spheroid cell growth and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven-amino-acid peptide derived from ANGEL2, rescued wild-type (WT) TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RNA-binding motif protein 38 complex to enhance WT TP53 translation, and furthermore, the Pep7 peptide may be explored as a therapeutic strategy for cancers that harbor WT TP53 expression.</p><p><strong>Implications: </strong>Loss of ANGEL2 contributes to decreased WT TP53 translation promoting doxorubicin resistance, which can be rescued via an ANGEL2-derived peptide.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"585-596"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.","authors":"Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0546","DOIUrl":"10.1158/1541-7786.MCR-24-0546","url":null,"abstract":"<p><p>Small cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. In this study, we show that kinase suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony-forming ability of tumor-propagating cells in vitro and their tumor-initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor-propagating cell function and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of SCLC-A tumors and a potential subtype-specific therapeutic target.</p><p><strong>Implications: </strong>Manipulation of the molecular scaffold KSR2 in SCLC-A cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"640-652"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empty Spiracles Homeobox 2 Transcription Factor Functions as a Tumor Suppressor in Renal Cell Carcinoma by Targeting CADM1.","authors":"Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang","doi":"10.1158/1541-7786.MCR-24-0496","DOIUrl":"10.1158/1541-7786.MCR-24-0496","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of empty spiracles homeobox 2 (EMX2) in patients with RCC and revealed a significant reduction of EMX2 expression, correlating with a poor prognosis in patients with RCC. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA sequencing and chromatin immunoprecipitation sequencing analyses, we have identified cell adhesion molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates caspase-3-dependent apoptosis in attached RCC cells. Furthermore, the EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by the EMX2-CADM1 axis promote RCC cell death and suppress its growth and invasion, providing potential intervention strategies for combating RCC.</p><p><strong>Implications: </strong>The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in RCC, which could lead to more effective treatment strategies for this aggressive malignancy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"597-610"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT.","authors":"Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew Donson, Ilango Balakrishnan, Natalie Serkova, Hening Lin, Nicholas K Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar","doi":"10.1158/1541-7786.MCR-24-0926","DOIUrl":"10.1158/1541-7786.MCR-24-0926","url":null,"abstract":"<p><p>An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency-differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.</p><p><strong>Implications: </strong>SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"515-529"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}